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    DNA damage and induction of apoptosis in pancreatic cancer cells by a new dinuclear bis(triazacyclonane) copper complex


    Montagner, Diego and Gandin, Valentina and Marzano, Cristina and Erxleben, Andrea (2015) DNA damage and induction of apoptosis in pancreatic cancer cells by a new dinuclear bis(triazacyclonane) copper complex. Journal of Inorganic Biochemistry, 145. pp. 101-107. ISSN 0162-0134

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    Abstract

    The dinuclear copper(II) complex [Cu2{bcmp(-H)}(μ-OH)](NO3)2·H2O (1, bcmp=2,6-bis(1,4,7-triazacyclonon- 1-ylmethyl)-4-methylphenol) has been synthesized and characterized by electrospray ionization mass spectrometry, potentiometric titration and cyclovoltammetry. The X-ray structure of the analogous perchlorate salt [Cu2{bcmp(-H)}(μ-OH)](ClO4)2·2.5H2O (2) was determined. Cytotoxicity studies showed very promising activity of 1 against various pancreatic tumor cell lines with IC50 values comparable or even lower than those of cisplatin. The Cu complex displayed low toxicity against a human non-tumor cell line (HEK 293) demonstrating selectivity for cancer cells. 1 converts supercoiled pUC19 plasmid DNA into the nicked form at micromolar concentrations in the absence of added reductants. A detailed kinetic study on the hydrolysis of the DNA model bis(2,4-dinitrophenyl) phosphate (BDNPP) has been performed. 1 hydrolyses BDNPP with a second order rate constant of 0.047Ms−1 at pH 8 and 40 °C. Finally, single cell electrophoresis (comet assay) and fluorescence microscopy analysis showed that 1 interacts with cellular DNA and induces apoptotic cell death of Capan-1 pancreatic cancer cells.Western blotting analysis indicated that the Cu complex activates the p53 dependent pathway of apoptosis.

    Item Type: Article
    Keywords: Copper; Cytotoxicity; DNA damage; Metallodrugs;
    Academic Unit: Faculty of Science and Engineering > Chemistry
    Item ID: 7817
    Identification Number: https://doi.org/10.1016/j.jinorgbio.2015.01.013
    Depositing User: Diego Montagner
    Date Deposited: 26 Jan 2017 16:46
    Journal or Publication Title: Journal of Inorganic Biochemistry
    Publisher: Elsevier
    Refereed: Yes
    Funders: European Commission, Science Foundation Ireland (SFI)
    URI:

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